Molecular mechanisms underlying the corneal endothelial pump

Abstract

The corneal endothelium is responsible for maintaining the hydration of the cornea. This is through a "Pump-Leak" mechanism where the active transport properties of the endothelium represent the "Pump" and the stromal swelling pressure represents the "Leak". For the "Pump", Na(+), K(+) ATPase activity and the presence of HCO(3)(-), Cl(-), and carbonic anhydrase activity are required. Several basolateral (stromal side) anion transporters, apical (facing the aqueous humor) ion channels and water channels have been identified that could support a model for ion secretion as the basis for the endothelial pump, however evidence of sustained anion fluxes, osmotic gradients or the need for water channels is lacking. This has prompted consideration of other models, such as Electro-osmosis, and consideration of metabolite flux as components of the endothelial pump. Although the conditions under which the "Pump" is supported are known, a complete model of the endothelial "Pump" has yet to emerge.

Figure 1

Bicarbonate Secretion Model for Endothelial Pump. Fluid coupled anion secretion requires transendothelial net flux of Cl⁻ and/or HCO₃⁻. The movement of net negative charge creates a small potential difference (0.5 mV, apical side negative) that attracts Na⁺through the paracellular pathway& across the tight junction (TJ). The net flux of NaHCO₃⁻and/or NaCl constitutes the osmotic driving force for water movement. HCO₃⁻ uptake on the basolateral membrane is through the actions of the 1Na⁺:2HCO₃⁻cotransporter (NBCe1) and the Na⁺/H⁺exchanger (NHE1). Cl⁻ uptake is primarily via the Na⁺:K⁺:2Cl⁻cotransporter (NKCC1) and the Cl⁻/HCO₃⁻exchanger (AE2). The high intracellular [Cl⁻]and[HCO₃⁻], together with the negative membrane potential can then drive anions across the apical membrane through anion selective channels. An additional route for net HCO₃⁻ flux is for the high intracellular [HCO₃⁻] to be converted to CO₂, facilitated by carbonic anhydrase II (CAII), apical CO₂ diffusion and conversion back to HCO₃⁻, facilitated by carbonic anhydrase IV (CAIV) at the apical surface. This pathway is less attractive because it does not contribute to the transendothelial potential.

Figure 2

Facilitated Lactate Transport Model. The bulk movement of lactic acid from cornea to anterior chamber via transcellular Monocarboxylate Cotransporters (MCTs) could contribute to net fluid movement out of the cornea. Intracellular buffering by the high intracellular [HCO₃⁻], provided by the 1Na⁺:2HCO₃⁻(NBCe1), Na⁺/H⁺exchanger (NHE1), and carbonic anhydrase II work to facilitate basolateral lactate:H⁺entry. Apical efflux through an MCT is facilitated by robust apical surface buffering, which is supplied by aqueous humor HCO₃⁻ and apical surface carbonic anhydrase IV.